The opioid agonist morphine decreases the dyskinetic response to dopaminergic agents in parkinsonian monkeys

www.elsevier.com/locate/ynbdi Neurobiology of Disease 16 (2004) 246 – 253

The opioid agonist morphine decreases the dyskinetic response to dopaminergic agents in parkinsonian monkeys Pershia Samadi, Laurent Gre´goire, and Paul J. Be´dard * Centre de recherche en Neuroscience, Centre Hospitalier Universitaire de Que´bec, Ste-Foy, Que´bec, Canada G1V4G2 Department of Medicine, Faculty of Medicine, Laval University, Que´bec, Canada Received 26 August 2003; revised 24 November 2003; accepted 4 February 2004 Available online 28 March 2004 In parkinsonian patients as well as in primate models with levodopainduced dyskinesias (LID), an increase in the expression of preproenkephalin in the striatal output pathways has been demonstrated. Does this increase contribute to the development of LID, or does it rather act as a protection mechanism? To clarify this question, we have investigated the effect of different doses of morphine on the dyskinetic response to L-DOPA, a D2 agonist, and a D1 agonist. We have used MPTP-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA. Co-administration of morphine with dopaminergic agents produces a significant reduction in the severity of dyskinesias, while it does not affect the antiparkinsonian efficacy of the treatment. This study suggests that the increased production of opioids in the striatal projection neurons might have a protective role to compensate the changes in synaptic transmissions that are responsible for dyskinesias, rather than be the cause of dyskinesias. D 2004 Elsevier Inc. All rights reserved. Keywords: Basal ganglia; Parkinson; Dyskinesias; Dopamine; Opioids

Introduction Parkinson’s disease (PD) is a progressive motor disorder that is characterized by degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) that innervate the striatum. Dopamine-replacement therapy with levodopa improves the cardinal symptoms of PD: bradykinesia, rigidity, tremor, and to a lesser extent alteration of postural reflexes. However, in a majority of patients, the therapy is associated with development of involuntary movements termed dyskinesias (Blanchet et al., 1996; Marsden, 1994). The role of cortico-basal ganglia-thalamo-cortical loops in the triggering of motor complications is known to be critical (Obeso et al., 2000). However, the exact neurochemical mechanisms involved in levodopa-induced dyskinesias (LID) are not well understood. * Corresponding author. Centre de recherche en Neuroscience, Centre Hospitalier Universitaire de Que´bec, Pavillon CHUL, 2705 Boulevard Laurier, Ste-Foy, Que´bec, Canada G1V4G2. Fax: +1-418-654-2753. E-mail address: [email protected] (P.J. Be´dard). Available online on ScienceDirect (www.sciencedirect.com.) 0969-9961/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2004.02.002

The striatum, the input structure of the basal ganglia, has two major output pathways, namely the direct (striatonigral) and indirect (striatopallidal) pathways. The normal function of the basal ganglia is dependent on the balanced activity of these two pathways (Parent et al., 2000). Direct GABAergic striatonigral neurons co-express dopamine (DA) D1 receptors, adenosine A1 receptors, and neuropeptides substance P and dynorphin. Indirect GABAergic striatopallidal neurons coexpress DA D2 receptors, adenosine A2a receptors, and the neuropeptide enkephalin (Fuxe et al., 1998; Parent et al., 2000). Intriguingly, the basal ganglia contain one of the highest levels of endogenous opioids in the brain and in the striatum; mRNA expression for all three opioid receptors A, y, n, was observed (Peckys and Landwehrmeyer, 1999). Preproenkephalin-A (PPE-A)-derived opioids, Met-enkephalin, Leu-enkephalin, Met-enkephalin heptapeptide, and Met-enkephalin octapeptide, are relatively selective agonists for y opioid receptors (Comb et al., 1982; Dhawan et al., 1996). Preproenkephalin-B (PPE-B) can produce a variety of opioids depending on the peptidases present. The peptides, dynorphins, Leu-enkephalin, and a-neoendomorphin are the endogenous ligands for n, y, and A opioid receptors, respectively (Kieffer, 1995). Studies of various animal models of PD have described that nigrostriatal denervation is associated with an increase of PPE-A mRNA expression, the precursor of enkephalin, in the striatopallidal neurons (Gerfen et al., 1990; Morissette et al., 1997, 1999; Zeng et al., 1995). However, PPE-B mRNA expression is unaltered (Duty et al., 1998; Meissner et al., 2003) or decreased in the striatonigral neurons (Gerfen et al., 1991; Li et al., 1990; Voorn et al., 1994). Recently, the causal link between striatal PPE-A gene expression and parkinsonian motor deficits has been questioned. It was shown that an increase in PPE-A gene expression can be observed without parkinsonian signs (Bezard et al., 2001; Schroeder and Schneider, 2000). On the other hand, following chronic MPTP treatment, while the motor impairment is still present, the expression of PPE-A is returned to control levels (Schneider et al., 1999). Therefore, it was suggested that increased enkephalinergic transmission might be involved in a regulatory process rather than be the cause of parkinsonian symptoms (Meissner et al., 2003; Schneider et al., 1999). Levodopa therapy in parkinsonian patients, as well as in primate-MPTP animal models of LID, is associated with an

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increase in the expression of PPE-A and PPE-B (Brotchie et al., 1998; Calon et al., 2002; Morissette et al., 1997, 1999). It has been suggested that enhanced opioidergic transmission in striatal pathways may play a role in the induction of dyskinesias (Brotchie, 1998; Henry and Brotchie, 1996). In contrast, more recently, the causal link between elevation of PPE expression and the development of LID in PD has been challenged (Quik et al., 2002). Furthermore, there is controversy in the literature about the effects of co-administration of opioid receptor agonists and antagonists with L-DOPA (Berg et al., 1999; Henry et al., 2001; Manson et al., 2001; Rascol et al., 1994). Therefore, the main and not yet clearly answered question concerns the role of enhanced opioid transmission. Could this increase be a consequence of levodopa therapy and act as a protection mechanism to attenuate LID rather than be the cause of LID? To clarify this point and to follow our previous results indicating that co-administration of opioid antagonists with dopaminergic agents increase the dyskinetic response in parkinsonian monkeys (Samadi et al., 2003), in this study we have investigated the effect of different doses of the nonselective opioid receptor agonist, morphine, on the dyskinetic response to L-DOPA, the D2 receptor agonist, quinpirole, and the D1 receptor agonist, SKF 82958.

Materials and methods Animals and pretreatments The experiments were performed with six adult bred female cynomolgus (Macaca fascicularis) monkeys weighing 3.7 – 5.1 kg. The animals were handled in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals, and all procedures were approved by the Institutional Animal Care Committee of Laval University. The animals were housed separately in observation cages and exposed to a 12h light/dark cycle (lights on, 6:00 AM to 6:00 PM) in a temperature-controlled room, 23 F 1jC. They were fed once daily in the afternoon with pellets and fruits and had free access to water. Before the experiments, all animals were exposed to subcutaneous injections of the neurotoxin MPTP at weekly interval (2 – 3 mg per injection) until a bilateral stable parkinsonian syndrome developed (i.e., unchanged parkinsonian score of 8 or more, over at least a month, see below in Evaluation of the response). The total dose and the time necessary to obtain sustained parkinsonian features varied between 9 and 23.5 mg and 4 and 32 weeks, respectively. Each animal was then treated orally, once daily, with L -DOPA/benserazide (100/25 mg; ProlopaR) (Hoffmann-La Roche, Mississauga, Ontario) during a few months, until dyskinesias, with a predominantly choreic nature, developed. The dyskinesias were thereafter reproduced upon subsequent doses of L-DOPA/benserazide or dopamine receptor agonists. To maintain priming and for their comfort, the monkeys received an oral dose of L-DOPA/benserazide two or three times a week. Experimental treatments L-DOPA methyl ester (Sigma, St. Louis, MO), always together with benserazide (50 mg; Hoffmann-La Roche, Montreal, Quebec) and quinpirole (Sigma), a selective D2 DA receptor agonist, at doses ranging between 20 – 25 and 0.03 – 0.1 mg/kg, respectively

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(based on the threshold concentration for each animal), were dissolved in 1 ml of 0.9% sterile saline and administered subcutaneously alone or in combination with morphine. SKF 82958 (Sigma), a selective D1 DA receptor agonist at doses ranging between 0.3 and 0.8 mg/kg (based on the threshold concentration for each animal) was dissolved in 1 ml of sterile water and administered subcutaneously alone or 15 min after morphine administration. Morphine (morphine sulfate 10 mg/1 ml, Abbott, Toronto), a nonselective opioid receptor agonist, was diluted in 0.9% sterile saline and administered subcutaneously at increasing doses 0.05, 0.2, 0.5, and 1 mg/kg in combination with dopaminergic agents. A subcutaneous injection of saline or morphine alone at the dose of 1 mg/kg was used as control. The experiments were performed at interval of 3 days (2 days per week), and during these intervals, the animals received only one oral dose of L-DOPA/ benserazide. Evaluation of the response On experimental days, the drugs were injected in the morning and the spontaneous behavior of the animals was assessed through a one-way screen and scored every 15 min according to a parkinsonian disability scale and a dyskinesia scale described below, for up to 4 h (during the ON state) without being disturbed. The time of administration of each treatment as well as the appearance and the end of the antiparkinsonian and dyskinetic responses was recorded to evaluate the latency and the duration of the dyskinesias and the antiparkinsonian effect. Short videotaped sequences were taken for all experiments and the results confirmed globally in terms of increase or decrease by another expert who was blind to the animal’s treatment. Dyskinesias The severity of dyskinesias was rated for the face, neck, trunk, arms, and legs in the following way: none = 0; mild = 1; moderate = 2; severe = 3, based on the assessment of the amplitude, interference with normal motor activity, and the frequency of the abnormal movements, according to a scale that we have used in several published studies (Hadj Tahar et al., 2001). The dyskinetic score obtained was the sum of the scores for all body segments for a maximal score of 21 points. The mean dyskinetic score for each animal has been calculated as the average of all the scores obtained for the total duration of the effect of the drugs and these nonparametric results are presented as a median score. Parkinsonian syndrome The parkinsonian syndrome for each animal was assessed before and after the treatments for a maximal disability score of 16, according to a scale that we have used in several published studies (Hadj Tahar et al., 2001). It includes assessment of (a) posture: normal = 0, flexed intermittent = 1, flexed constant = 2, crouched = 3; (b) mobility: normal = 0, mild reduction = 1, moderate reduction = 2, severe reduction = 3; (c) climbing: present = 0, absent = 1; (d) gait: normal = 0, slow = 1, very slow = 2, very slow with freezing = 3; (e) grooming: present = 0, absent = 1; (f) voicing: present = 0, absent = 1; (g) social interaction: present = 0, absent = 1; (h) tremor: absent = 0, mild action tremor = 1, moderate action tremor = 2, resting tremor = 3. The mean parkinsonian score for each animal has been calculated as average of all the scores obtained for the total duration of the

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effect of drugs, while minimum parkinsonian score was the minimum score observed in this period. These data are expressed as a median score. Locomotor activity Locomotor activity was quantified using an electronic motility monitoring system (Datascience, St. Paul, MN). Using radio wave frequency, a probe around the neck of each animal transmits the signal to a receiver fixed on each cage. This receiver is connected to a computer and provides a motility count every 5 min. Statistical analysis The mean and the minimum parkinsonian scores and also the mean dyskinetic scores obtained for each monkey, during the total duration of the effect of a given drug, were analyzed using the nonparametric Friedman’s test followed by multiple comparisons based on Friedman rank sums. For locomotor activity, to obtain homogeneity of variance, we used the logarithm of total mobility counts recorded for each animal during the ON state following a given treatment. These data for all monkeys were compared using an analysis of variance (ANOVA) for repeated measures followed by a Fisher’s probability of least significant differences (PLSD).

Results Dyskinetic response to dopaminergic agents alone or in combination with morphine Co-administration of morphine at all doses, 0.05, 0.2, 0.5, and 1 mg/kg, with L-DOPA/benserazide decreased significantly the intensity of dyskinesias for the total duration of the effect of drugs (Figs. 1A, 5A). Quinpirole and SKF 82958 administered alone induced dyskinesias that were significantly decreased by their combination with morphine at 0.2 and 1 mg/kg for the total duration of the effect of drugs (Figs. 1B, C and 5B, C). Coadministration of morphine had no effect on the time course of the dyskinesias induced by L-DOPA/benserazide, quinpirole, and SKF 82958 (Figs. 5A – C). Dyskinesias induced by L-DOPA, quinpirole, or SKF 82958 alone or in combination with morphine were mainly choreoathetotic, but dystonia was also observed. These dyskinetic movements were seen mainly in the upper and lower limbs and trunk, in the neck in some animals, and rarely in the face. Anti-parkinsonian response to dopaminergic agents alone or in combination with morphine Parkinsonian score Administration of L-DOPA/benserazide, quinpirole, or SKF 82958 alone improved significantly the parkinsonian score compared to the controls (saline and morphine 1 mg/kg). Cotreatment of morphine with the mentioned dopaminergic agents did not have any effect on the improvement of parkinsonian response induced by these drugs alone (Figs. 2A, 3A, 4A). In addition, morphine did not change the duration of the anti-parkinsonian response to L-DOPA/benserazide, quinpirole, and SKF 82958 (Figs. 5D – F).

Fig. 1. Dyskinetic response to L-DOPA/benserazide (A), quinpirole (B), and SKF 82958 (C) alone or in combination with morphine. Each point represents the mean dyskinetic scores for the total duration of the effect of the drugs for each monkey, expressed as the percentage of control. The data analysis was done using the nonparametric Friedman’s test followed by multiple comparisons based on Friedman rank sums. The horizontal line illustrates the median score. *P < 0.05 versus L-DOPA and **P < 0.01 versus L-DOPA, quinpirole, or SKF 82958.

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Fig. 2. Anti-parkinsonian response to L-DOPA/benserazide alone or in combination with morphine. (A) Each bar represents the range of mean or minimum parkinsonian scores for all animals during the total effect of drug treatments. These scores were analyzed using the nonparametric Friedman’s test followed by multiple comparisons based on Friedman rank sums. The horizontal line indicates the median score. They are all significantly different from saline and morphine with P < 0.01. There is no difference between the parkinsonian scores obtained after co-administration of morphine with L-DOPA compared with LDOPA alone. (B) The logarithms of the total locomotor activity counts recorded individually during 2 h 30 after each treatment were averaged for all animals. The values were compared using ANOVA for repeated measures followed by Fisher’s PLSD test. Log counts F SEM. yP < 0.05 and yyP < 0.01 versus saline and morphine. There was no significant difference in locomotor activity after L-DOPA administration alone or in cotreatment with morphine. Mean park: mean parkinsonian score. Min park: minimum parkinsonian score.

Locomotor activity Locomotor activity was increased significantly after L-DOPA/ benserazide, quinpirole, SKF 82958 administration versus saline, and morphine alone (1 mg/kg). There was no significant difference in locomotion between all dopaminergic treatments alone and their combination with morphine (Figs. 2B, 3B, 4B). The duration of the effect of L-DOPA/benserazide and quinpirole ranged from 2 to 3 h 30 and morphine was injected

simultaneously with these drugs. However, as the duration of the effect of SKF 82958 is short (maximum of 1 h with the mentioned doses), SKF was injected 15 min after morphine. Sleepiness or licking was not observed during these treatments. The co-administration of the opioid agonist, morphine, had no effect on the latency or duration of dyskinesias and anti-parkinsonian responses induced by L-DOPA, quinpirole, and SKF 82958.

Fig. 3. Anti-parkinsonian response to quinpirole administration alone or in combination with morphine. (A) Mean and minimum parkinsonian scores during the total effect of drug treatments were obtained as described in Fig. 2A. The horizontal line shows the median score. All are significantly different from saline and morphine with P < 0.01. Co-administration of morphine with quinpirole did not have any effect on the anti-parkinsonian response to quinpirole. (B) The logarithm of total mobility counts during 2 h after each treatment for all monkeys was obtained as explained in Fig. 2B. Log counts F SEM. yyP < 0.01 versus saline and morphine. There was no significant difference in locomotion after quinpirole administration alone and in combination with morphine.

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Fig. 4. Anti-parkinsonian response to SKF 82958 administration alone or in combination with morphine. (A) Mean and minimum parkinsonian scores during the total duration of the effect of the drug were obtained as explained in Fig. 2A. The horizontal line represents the median score. They are all significantly different from saline and morphine with P < 0.01. Co-administration of SKF 82958 with morphine did not have any effect on the anti-parkinsonian response to SKF 82958 alone. (B) The logarithm of total mobility counts during 1 h after each treatment for all monkeys was obtained as explained in Fig. 2B. Log counts F SEM. yyP < 0.01 versus saline and morphine. The combination of morphine with SKF 82958 had no significant effect on the increased locomotor activity induced by administration of SKF 82958 alone.

Fig. 5. The time course of dyskinetic and anti-parkinsonian responses to L-DOPA/benserazide (A, D), quinpirole (B, E), and SKF 82958 (C, F) alone or in combination with morphine. Each point represents the average of the dyskinetic or the anti-parkinsonian scores for all monkeys.

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Discussion The present results indicate that co-administration of morphine with dopaminergic agents in parkinsonian dyskinetic monkeys leads to a significant decrease in the severity of dyskinesias without any effect on the anti-parkinsonian efficacy of the treatments. Cotreatment of morphine at the dose of 0.5 mg/kg with quinpirole or SKF 82958 did not decrease significantly the dyskinetic response. The reason of this effect might be tolerance to morphine, because with the higher dose of morphine (1 mg/kg), the dyskinetic response was again decreased significantly. Our results are in agreement with clinical studies that demonstrated that morphine could reduce dyskinesias in PD patients (Berg et al., 1999). The differences of our observations with other studies (Henry et al., 2001) may be related to species differences between the cynomolgus monkeys used in our studies and the marmoset monkeys in the other. It is possible that lower species of primates have a different repertoire of movement disorders in which hyperkinesia predominates. It is also likely that hyperkinesia responds differently to opiates and opioid antagonists decrease hyperkinesia, while in higher species of primates, morphine reduces dyskinesias. Dopaminergic and glutamatergic systems interact closely at the level of medium spiny output neurons. The cortical input to the striatum is massive and topographically organized. Glutamatergic cortical afferents synapse specially on the head of dendritic spines of medium spiny neurons, whereas dopaminergic nigrostriatal neurons synapse mainly onto the shafts of the same dendritic spines (Smith and Bolam, 1990). These findings suggest that glutamate activates medium spiny neurons and DA modulates striatal glutamatergic input (Pollack, 2001; Starr, 1995). In LID, changes in the firing patterns of corticostriatal neurons are thought to play a crucial role in corticostriatal-mediated synaptic plasticity and may thus be important in the origin of dyskinesias (Hadj Tahar et al., 2003; Obeso et al., 2000). The increase of PPE mRNA expression observed in human parkinsonian patients, MPTP monkeys, and 6-OHDA rats are mostly observed in the sensorimotor area of the striatum that receives the projection from sensorimotor cortex regions (Calon et al., 2002; Duty et al., 1998; Morissette et al., 1997, 1999). It is demonstrated that in the DA-denervated striatum, the input from the prefrontal cortex is one of the primary influences that maintain increased PPE expression (Campbell and Bjorklund, 1994). Accordingly, blockade of NMDA receptors suppresses the effects of nigrostriatal DA deafferentation on increased enkephalin expression in the striatum (Hajji et al., 1996). Therefore, the corticostriatal afferents may participate in the regulation of striatal neuropeptide expression (Campbell and Bjorklund, 1994; Hajji et al., 1996; Schneider et al., 1999). The colocalization of NMDA and A opioid receptors within patches (Wang et al., 1999) and the distribution of y opioid receptors through patch and matrix (Mansour et al., 1987) have been demonstrated. Interestingly, it was suggested that opioid receptors within the striatum play an important role in modulating the presynaptic release of glutamate (Wang and Pickel, 2001). Furthermore, electrophysiological studies also suggest that the main action of opioids on striatal neurons is presynaptic inhibition of excitatory corticostriatal input (Jiang and North, 1992). Since our present and previous results (Samadi et al., 2003) demonstrate that opioid agonists and antagonists decrease and increase the dyskinetic response to dopaminergic agents, respec-

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tively, we might conclude that in LID, as the physiological modulation of glutamatergic corticostriatal input by dopaminergic neurons is deficient, the expression of PPE-A and PPE-B could be an adaptive or compensatory response to dampen the effect of corticostriatal overactivity associated with LID. Furthermore, it was proposed that N-methyl- D -aspartate (NMDA) increases cAMP levels via increased intracellular Ca2+ levels, adenosine formation, and stimulation of adenosine A2a receptors (Nash and Brotchie, 2000). As all opioid receptor subtypes inhibit Ca2+ currents (Williams et al., 2001), activation of opioid receptors may have opposite effects on Ca+ influx and cascade signaling. One of the other actions of opioids at the cellular level is inhibition of adenylate cyclase and reduction of intracellular cAMP levels (Williams et al., 2001). It was demonstrated that A opioid agonists through the decrease of cAMP level and consequently attenuation of protein kinase A (PKA)-mediated phosphorylation of NMDA channels or associated regulatory proteins could inhibit NMDA glutamate receptor currents in the postsynaptic neuron (Xie and Lewis, 1997). Interestingly, a protein kinase A (PKA) inhibitor dampens the intensity of levodopa-induced alterations in motor response (Oh et al., 1997). Interaction of DA and adenosine may also contribute to the regulation of PPE-A and PPE-B in the striatal output pathways (Halimi et al., 2000; Lindskog et al., 1999; Schiffmann and Vanderhaeghen, 1993). Adenosine A1 and A2a receptor activation antagonize DA D1 and D2 receptor-mediated actions on GABAergic transmission, respectively (Fuxe et al., 1998). Dopamine, via D1 receptors, and adenosine, via A2a receptors, increase the level of cAMP and consequently cause the activation of protein kinases and phosphorylation of dopamine and cAMP-regulated phosphoprotein (DARPP-32) on Thr-34 in the two major striatal output pathways (Svenningsson et al., 1998). The phosphorylation converts DARPP-32 from an inactive molecule into an inhibitor of protein phosphatase-1 (PP-1), which controls the state of phosphorylation and activity of numerous physiologically important effectors including transcription factors such as cAMP-response element binding protein (CREB) and Fos-family (Greengard, 2001). Modification of immediate early genes (IEG) or late-onset genes (LOG), following activation of transcription factors, might trigger the short- and long-term adaptive changes that are responsible for abnormal responses to dopaminergic agents, that in primates and humans translate into the emergence of dyskinesias (Be´dard et al., 1999). It was demonstrated that A and y opioid receptor agonists prevent the D1 and A2a receptor-mediated increase in cAMP in striatonigral and striatopallidal neurons, respectively (Lindskog et al., 1999). Intriguingly, recent findings also reveal that the loss of depotentiation observed in dyskinetic animals is accompanied by abnormally high levels of Thr-34phosphorylated DARPP-32 compared with nondyskinetic and drug-naive controls (Picconi et al., 2003). Accordingly, the results of the present work in agreement with our previous results, which demonstrated that antagonizing the action of opioid receptors increases the involuntary movements in parkinsonian monkeys, suggest that the cAMP signaling cascade might play a key role for mediating LID and the increase in opioid transmission might be a mechanism to dampen the increase in cAMP signaling cascade. Conclusion Our results suggest that the increased production of opioids in the direct and indirect striatal projection neurons, observed in

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parkinsonian patients or MPTP monkeys with LID, might have a protective role to compensate the changes in synaptic transmission that are responsible for dyskinesias, rather than be the cause of dyskinesias. The present observations could provide new elements for understanding the role of opioid transmission in LID. In addition, it may suggest therapeutic interventions for development of drugs that target opioid receptor activation while minimizing tolerance.

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